Rapid synthesis and in situ screening of potent HIV-1 protease dimerization inhibitors

Chemistry & Biology
Song-Gil Lee, Jean Chmielewski

Abstract

A library of dimerization inhibitors of HIV-1 protease is described based on crosslinked interfacial peptides. The 54 component library was designed to contain two modifications to the starting structure, one each in the Northern and Southern fragments. A rapid synthesis and in situ screening method in microtiter plates was developed to facilitate the generation and evaluation of the library members. More than 90% of the doubly modified agents were more potent than their respective singly mutated parent compounds, and five of the most potent dimerization inhibitors of HIV-1 protease described to date were identified. The free energy of binding for the combined two modifications was generally found to be additive, demonstrating the predictive value of earlier libraries.

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Citations

Jul 28, 2009·Nature Chemical Biology·Tina ShahianCharles S Craik
Apr 1, 2009·Future Medicinal Chemistry·Giovanna Zinzalla, David E Thurston
Mar 25, 2011·Future Medicinal Chemistry·Obdulia RabalJulen Oyarzabal
Sep 16, 2015·Expert Opinion on Drug Discovery·Boshi HuangXinyong Liu
Apr 1, 2008·Biophysical Journal·Gennady VerkhivkerRicardo A Broglia
Feb 11, 2021·Organic & Biomolecular Chemistry·Jian FuStéphane P Vincent
Apr 15, 2008·Organic Letters·Peng-Yu YangShao Q Yao
May 7, 2008·Organic Letters·Rajavel SrinivasanShao Q Yao
Mar 9, 2012·The Journal of Organic Chemistry·T M VishwanathaVommina V Sureshbabu
Mar 14, 2008·Bioorganic & Medicinal Chemistry·Michael J Bowman, Jean Chmielewski

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